tbuckley/cabot-search huggingface dataset:
Bosutinib in Resistant and Intolerant Pediatric Patients With Chronic Phase Chronic Myeloid Leukemia: Results From the Phase I Part of Study ITCC054/COG AAML1921
Authors: Erica Brivio, Edoardo Pennesi, Marieke E. Willemse, Alwin D.R. Huitema, Yilin Jiang, Harm D.R. van Tinteren, Vincent H.J. van der Velden, Berna H. Beverloo, Monique L. den Boer, Lukas A.J. Rammeloo, Chad Hudson, Nyla Heerema, Karey Kowalski, Huadong Zhao, Luke Kuttschreuter, Francisco J. Bautista Sirvent, Andrew Bukowinski, Carmelo Rizzari, Jessica Pollard, Laura Murillo-Sanjuán, Matthew Kutny, Sara Zarnegar-Lumley, Michele Redell, Stacy Cooper, Yves Bertrand, Arnaud Petit, Julie Krystal, Markus Metzler, Donna Lancaster, Jean-Pierre Bourquin, Jayashree Motwani, Inge M. van der Sluis, Franco Locatelli, Michael E. Roth, Nobuko Hijiya, Christian M. Zwaan
Journal: Journal of Clinical Oncology (2023)

Bosutinib is approved for adults with chronic myeloid leukemia (CML): 400 mg once daily in newly diagnosed (ND); 500 mg once daily in resistant/intolerant (R/I) patients. Bosutinib has a different tolerability profile than other tyrosine kinase inhibitors (TKIs) and potentially less impact on growth (preclinical data). The primary objective of this first-in-child trial was to determine the recommended phase II dose (RP2D) for pediatric R/I and ND patients.
High-frequency home self-collection of capillary blood correlates IFI27 expression kinetics with SARS-CoV-2 viral clearance
Authors: Fang Yun Lim, Soo-Young Kim, Karisma N. Kulkarni, Rachel L. Blazevic, Louise E. Kimball, Hannah G. Lea, Amanda J. Haack, Maia S. Gower, Terry Stevens-Ayers, Lea M. Starita, Michael Boeckh, Ollivier Hyrien, Joshua T. Schiffer, Ashleigh B. Theberge, Alpana Waghmare
Journal: Journal of Clinical Investigation (2023)
Intranasal immunization with an RBD-hemagglutinin fusion protein harnesses preexisting immunity to enhance antigen-specific responses
Authors: Atsushi Kawai, Nagisa Tokunoh, Eigo Kawahara, Shigeyuki Tamiya, Shinya Okamura, Chikako Ono, Jessica Anindita, Hiroki Tanaka, Hidetaka Akita, Sho Yamasaki, Jun Kunisawa, Toru Okamoto, Yoshiharu Matsuura, Toshiro Hirai, Yasuo Yoshioka
Journal: Journal of Clinical Investigation (2023)

Intranasal vaccines are anticipated to be powerful tools for combating many infectious diseases, including SARS-CoV-2, because they induce not only systemic immunity but also mucosal immunity at the site of initial infection. However, they are generally inefficient in inducing an antigen-specific immune response without adjuvants. Here, we developed an adjuvant-free intranasal vaccine platform that utilizes the preexisting immunity induced by previous infection or vaccination to enhance vaccine effectiveness. We made RBD-HA, a fusion of the receptor-binding domain (RBD) of spike derived from SARS-CoV-2 as a vaccine target with HA derived from influenza A virus (IAV) as a carrier protein. Intranasal immunization of previously IAV-infected mice with RBD-HA without an adjuvant elicited robust production of RBD-specific systemic IgG and mucosal IgA by utilizing both HA-specific preexisting IgG and CD4+ T cells. Consequently, the mice were efficiently protected from SARS-CoV-2 infection. Additionally, we demonstrated the high versatility of this intranasal vaccine platform by assessing various vaccine antigens and preexisting immunity associated with a variety of infectious diseases. The results of this study suggest the promising potential of this intranasal vaccine platform to address problems associated with intranasal vaccines.
Inflammatory Tongue Conditions and Risk of Oral Tongue Cancer Among the US Elderly Individuals
Authors: Joseph E. Tota, Eric A. Engels, Mark W. Lingen, Nishant Agrawal, Alexander R. Kerr, Zachary S. Zumsteg, Li C. Cheung, Hormuzd A. Katki, Christian C. Abnet, Anil K. Chaturvedi
Journal: Journal of Clinical Oncology (2023)

PURPOSE The incidence of oral tongue cancers has increased since the 1980s among US men and women for unknown reasons. We investigated associations of inflammatory tongue conditions with risk of cancers of the oral tongue, other oral cavity, and oropharynx among the US elderly individuals (age 65 years or older). METHODS We conducted a case-control study (2,534 oral tongue cancers, 6,832 other oral cavity cancers, 9,373 oropharyngeal cancers, and 200,000 controls) within the SEER-Medicare data set (1992-2013). Medicare records were used to identify patients with clinically diagnosed inflammatory tongue conditions (glossitis, benign migratory glossitis, median rhomboid glossitis, atrophic glossitis, glossodynia, other specified conditions [eg, atrophy and hypertrophy], and other unspecified conditions) and oral precancer (leukoplakia/erythroplakia). Only conditions preceding cancer/control selection by &gt;12 months were included. RESULTS The prevalence of inflammatory tongue conditions was significantly higher in patients with tongue cancer than controls (6.0% v 0.6%; odds ratios [ORs], adjusted for age, sex, race, Medicare utilization, and precancer, 5.8 [95% CI, 4.7 to 7.2]). This overall association primarily arose from glossitis, 5.6 (95% CI, 4.4 to 7.2); other specified conditions, 9.1 (95% CI, 5.5 to 15.2); and other unspecified conditions, 13.7 (95% CI, 8.0 to 23.7). These associations remained strongly elevated &gt;5 years preceding tongue cancer (arguing against reverse causation), for conditions diagnosed by a specialist (arguing against misclassification), and among patients who received an oral biopsy (arguing against missed cancer). During 2013, an estimated 1 in 11 patients with oral tongue cancer had a preceding diagnosis of inflammatory tongue conditions. Associations of inflammatory tongue conditions were relatively weak for other oral cavity cancers (ORs, 1.8 [95% CI, 1.5 to 2.3]) and oropharyngeal cancer (OR, 1.3 [95% CI, 1.0 to 1.6]) and were observed only closest to cancer diagnosis. CONCLUSION Inflammatory tongue conditions were associated with strongly increased risks of oral tongue cancers and preceded cancer diagnosis by several years, underscoring the need for increased clinical surveillance among patients with such apparently benign diagnoses.
Deciphering and disrupting PIEZO1-TMEM16F interplay in hereditary xerocytosis
Authors: Pengfei Liang, Yang Zhang, Yui Chun S. Wan, Shang Ma, Ping Dong, Augustus J. Lowry, Samuel J. Francis, Sanjay Khandelwal, Martha Delahunty, Marilyn J. Telen, John J. Strouse, Gowthami M. Arepally, Huanghe Yang
Journal: Blood (2023)
CAR T-cell therapy in multiple myeloma: mission accomplished?
Authors: Leo Rasche, Michael Hudecek, Hermann Einsele
Journal: Blood (2023)

B-cell maturation antigen (BCMA) chimeric antigen receptor (CAR) T cells are the most potent treatment against multiple myeloma (MM). Here, we review the increasing body of clinical and correlative preclinical data that support their inclusion into firstline therapy and sequencing before T-cell-engaging antibodies. The ambition to cure MM with (BCMA-)CAR T cells is informed by genomic and phenotypic analysis that assess BCMA expression for patient stratification and monitoring, steadily improving early diagnosis and management of side effects, and advances in rapid, scalable CAR T-cell manufacturing to improve access.
Nonhormonal Male Contraceptive Development—Strategies for Progress
Authors: Logan Nickels, Wei Yan
Journal: Pharmacological Reviews (2023)

<h3>Abstract</h3> Despite the widely demonstrated public health benefits of contraception, limited contraceptive options are available for men, placing both the contraceptive burden and opportunity solely on women. This review outlines the need for an increased focus on male contraceptive development and highlights several related topics, including the perspectives of women and men on male contraceptives, historical challenges, and reasons behind the persistent delays in male contraceptive development. It also discusses the importance of serendipitous observations in drug discovery and the limitations of depleting sperm or spermatogenic cells as a contraceptive approach. It further provides an overview of ongoing research and development on novel methods, with a goal to offer insights into the multifaceted aspects of nonhormonal male contraceptive development, addressing its implications for the health of men and women. <h3>Significance Statement</h3> Despite well over half a century of effort in developing male contraceptives, there are no approved male contraceptive drugs on the market. This review aims to present strategies for progress in nonhormonal male contraception based on lessons learned from history, with the hope of expediting development and bringing a male contraceptive drug closer to reality.
Hematocrit: The Neglected Variable of Extracorporeal CO<sub>2</sub> Removal
Authors: Luigi Vivona, Michele Battistin, Eleonora Carlesso, Gaetano Florio, Serena Todaro, Sebastiano M. Colombo, Francesco Zadek, Giacomo Grasselli, Alberto Zanella, Thomas Langer
Journal: American Journal of Respiratory and Critical Care Medicine (2023)

"Hematocrit: The Neglected Variable of Extracorporeal CO2 Removal." American Journal of Respiratory and Critical Care Medicine, 209(5), pp. 595–598
Successful elimination of falciparum malaria following the introduction of community-based health workers in Eastern Myanmar: A retrospective analysis
Authors: Aye Sandar Zaw, Ei Shwe Sin Win, Soe Wai Yan, Kyaw Sithu Thein, Vasundhara Verma, Alistair R. D. McLean, Thar Tun Kyaw, Nicholas J. White, Frank M. Smithuis
Journal: PLoS Medicine (2023)

Background Myanmar has a large majority of all malaria in the Greater Mekong Subregion. In the past decade, substantial progress was made in malaria control. The residual burden of malaria is in remote areas where currently recommended malaria elimination approaches are generally not feasible. In such hard-to-reach communities in Mon state, East Myanmar, Medical Action Myanmar introduced community health workers (CHWs) to deliver early diagnosis and treatment for malaria. We conducted a retrospective analysis to assess the impact of this intervention. Methods and findings This retrospective analysis involved data collected routinely from a CHW programme in Mon state conducted between 2011 and 2018. A network of 172 CHWs serving a population of 236,340 was deployed. These CHWs carried out 260,201 malaria rapid diagnostic tests (RDTs) to investigate patients with acute febrile illness. The median blood examination rate was 1.33%; interquartile range (IQR) (0.38 to 3.48%); 95% CI [1.28%, 1.36%] per month. The changes in malaria incidence and prevalence in patients presenting with fever were assessed using negative binomial regression mixed effects models fitted to the observed data. The incidence of Plasmodium falciparum malaria (including mixed infections) declined by 70%; 95% CI [65%, 75%]; p &lt; 0.001 for each year of CHW operation. The incidence of P . vivax malaria declined by 56%; 95% CI [50%, 62%]; p &lt; 0.001 per year. Malaria RDT positivity rates for P . falciparum and P . vivax declined by 69%; 95% CI [62%, 75%]; p &lt; 0.001 and 53%; 95% CI [47%, 59%]; p &lt; 0.001 per year, respectively. Between 2017 and 2018, only 1 imported P . falciparum case was detected in 54,961 RDTs. The main limitations of the study are use of retrospective data with possible unidentified confounders and uncharacterised population movement. Conclusions The introduction of CHWs providing community-based malaria diagnosis and treatment and basic health care services in remote communities in Mon state was associated with a substantial reduction in malaria. Within 6 years, P . falciparum was eliminated and the incidence of P . vivax fell markedly.
Determinants and reference values for blood volume and total hemoglobin mass in women and men
Authors: Laura Oberholzer, David Montero, Paul Robach, Christoph Siebenmann, Camilla Koch Ryrsøe, Thomas C. Bonne, Andreas Breenfeldt Andersen, Jacob Bejder, Trine Karlsen, Elisabeth Edvardsen, Bent R. Rønnestad, Håvard Hamarsland, Ana C. Cepeda‐Lopez, Jörn Rittweger, Gunnar Treff, Christoph Ahlgrim, Nicki Winfield Almquist, Jostein Hallén, Carsten Lundby
Journal: American Journal of Hematology (2023)

Blood volume (BV) is an important clinical parameter and is usually reported per kg of body mass (BM). When fat mass is elevated, this underestimates BV/BM. One aim was to study if differences in BV/BM related to sex, age, and fitness would decrease if normalized to lean body mass (LBM). The analysis included 263 women and 319 men (age: 10-93 years, body mass index: 14-41 kg/m
Charcot Foot Offloading in Stage 0 Is Associated With Shorter Total Contact Cast Treatment and Lower Risk of Recurrence and Reconstructive Surgery: A Pilot Study
Authors: Johan Schoug, Per Katzman, Katarina Fagher, Magnus Löndahl
Journal: Diabetes Care (2023)

OBJECTIVE Charcot foot (CF) requires prolonged offloading of the affected foot to decrease the risk of deformity. The earliest phase in active CF (stage 0) is characterized by inflammatory signs without established fractures or skeletal deformity. We investigated whether offloading in stage 0 influences duration of total contact casting (TCC), risk of recurrence, and future need for surgery. RESEARCH DESIGN AND METHODS All patients treated for active CF at Skåne University Hospital (Lund, Sweden) between 2006 and 2019 were screened for participation in a retrospective cohort study. CF events of included patients were classified as stage 0 or 1 according to X-ray and MRI reports. RESULTS A total of 183 individuals (median age 61 [interquartile range (IQR) 52–68] years, 37% type 1 diabetes, 62% men) were followed for a median of 7.0 (IQR 3.9–11) years. In 198 analyzed CF events, 74 were treated with offloading in stage 0 and 124 in stage 1. Individuals offloading in stage 0 had significantly shorter TCC duration (median 75 [IQR 51–136] vs. 111.5 [72–158] days; P = 0.001). The difference was sustained when including only MRI-confirmed CF. The risk of developing new ipsilateral CF events &amp;gt;1 year after introduced definitive footwear was lower in those treated with offloading in stage 0 (2.7% vs. 9.7%; P &amp;lt; 0.05). No individual treated with offloading in stage 0 underwent reconstructive surgery, compared with 11 (8.9%) treated with offloading in stage 1 (P &amp;lt; 0.01). Amputation rates were similar. CONCLUSIONS Offloading in stage 0 CF was associated with shorter TCC treatment, lower risk of a new CF event, and diminished need for reconstructive surgery. Future amputation risk was not affected.
Erratum: “Prenatal Exposure to per- and Polyfluoroalkyl Substances, Umbilical Cord Blood DNA Methylation, and Cardio-Metabolic Indicators in Newborns: The Healthy Start Study”
Authors: Anne P. Starling, Cuining Liu, Guannan Shen, Ivana V. Yang, Katerina Kechris, Sarah J. Borengasser, Kristen E. Boyle, Weiming Zhang, Harry A. Smith, Antonia M. Calafat, Richard F. Hamman, John L. Adgate, Dana Dabelea
Journal: Environmental Health Perspectives (2023)
2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation
Authors: José A. Joglar, Mina K. Chung, Anastasia L. Armbruster, Emelia J. Benjamin, Janice Y. Chyou, Edmond M. Cronin, Anita Deswal, Lee L. Eckhardt, Zachary D. Goldberger, Rakesh Gopinathannair, Bulent Gorenek, Paul L. Hess, Mark Hlatky, Gail Hogan, Chinwe Ibeh, Julia H. Indik, Kazuhiko Kido, Fred Kusumoto, Mark S. Link, Kathleen T. Linta, Gregory M. Marcus, Patrick M. McCarthy, Nimesh Patel, Kristen K. Patton, Marco V. Perez, Jonathan P. Piccini, Andrea M. Russo, Prashanthan Sanders, Megan M. Streur, Kevin L. Thomas, Sabrina Times, James E. Tisdale, Anne Marie Valente, David R. Van Wagoner, Andrew D. Krahn, Jason G. Andrade, Craig J. Beavers, James M. Bischoff, T. Jared Bunch, Kristen Bova Campbell, Lin Yee Chen, Robin Dharia, Michael P. Dorsch, Edward P. Gerstenfeld, Aubrey E. Jones, Stephanie Dwyer Kaluzna, Luke Masha, Isabelle Nault, Peter A. Noseworthy, Cara N. Pellegrini, Stylianos E. Tzeis, Annabelle Santos Volgman, Emily P. Zeitler
Journal: Journal of the American College of Cardiology (2023)
Activation of the pentose phosphate pathway in macrophages is crucial for granuloma formation in sarcoidosis
Authors: Satoshi Nakamizo, Yuki Sugiura, Yoshihiro Ishida, Yoko Ueki, Satoru Yonekura, Hideaki Tanizaki, Hiroshi Date, Akihiko Yoshizawa, Teruasa Murata, Kenji Minatoya, Mikako Katagiri, Seitaro Nomura, Issei Komuro, Seishi Ogawa, Saeko Nakajima, Naotomo Kambe, Gyohei Egawa, Kenji Kabashima
Journal: Journal of Clinical Investigation (2023)

Sarcoidosis is a disease of unknown etiology in which granulomas form throughout the body and is typically treated with glucocorticoids, but there are no approved steroid-sparing alternatives. Here, we investigated the mechanism of granuloma formation using single-cell RNA-Seq in sarcoidosis patients. We observed that the percentages of triggering receptor expressed on myeloid cells 2-positive (TREM2-positive) macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, diagnostic makers of sarcoidosis, were increased in cutaneous sarcoidosis granulomas. Macrophages in the sarcoidosis lesion were hypermetabolic, especially in the pentose phosphate pathway (PPP). Expression of the PPP enzymes, such as fructose-1,6-bisphosphatase 1 (FBP1), was elevated in both systemic granuloma lesions and serum of sarcoidosis patients. Granuloma formation was attenuated by the PPP inhibitors in in vitro giant cell and in vivo murine granuloma models. These results suggest that the PPP may be a promising target for developing therapeutics for sarcoidosis.
Mechanistic engineering of celastrol liposomes induces ferroptosis and apoptosis by directly targeting VDAC2 in hepatocellular carcinoma
Authors: Piao Luo, Qian Zhang, Shuo Shen, Yehai An, Lixia Yuan, Yin-Kwan Wong, Sizhe Huang, Shaohui Huang, Jingnan Huang, Guangqing Cheng, Jiahang Tian, Yu Chen, Xiaoyong Zhang, Weiguang Li, Songqi He, Jigang Wang, Qingfeng Du
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Hepatocellular carcinoma (HCC) is one of most common and deadliest malignancies. Celastrol (Cel), a natural product derived from the Tripterygium wilfordii plant, has been extensively researched for its potential effectiveness in fighting cancer. However, its clinical application has been hindered by the unclear mechanism of action. Here, we used chemical proteomics to identify the direct targets of Cel and enhanced its targetability and anti-tumor capacity by developing a Cel-based liposomes in HCC. We demonstrated that Cel selectively targets the voltage-dependent anion channel 2 (VDAC2). Cel directly binds to the cysteine residues of VDAC2, and induces cytochrome C release via dysregulating VDAC2-mediated mitochondrial permeability transition pore (mPTP) function. We further found that Cel induces ROS-mediated ferroptosis and apoptosis in HCC cells. Moreover, coencapsulation of Cel into alkyl glucoside-modified liposomes (AGCL) improved its antitumor efficacy and minimized its side effects. AGCL has been shown to effectively suppress the proliferation of tumor cells. In a xenograft nude mice experiment, AGCL significantly inhibited tumor growth and promoted apoptosis. Our findings reveal that Cel directly targets VDAC2 to induce mitochondria-dependent cell death, while the Cel liposomes enhance its targetability and reduces side effects. Overall, Cel shows promise as a therapeutic agent for HCC.
A nanocomposite competent to overcome cascade drug resistance in ovarian cancer via mitochondria dysfunction and NO gas synergistic therapy
Authors: Min Zhong, Peiqin Liang, Zhenzhen Feng, Xin Yang, Guang Li, Rui Sun, Lijuan He, Jinxiu Tan, Yangpengcheng Xiao, Zhiqiang Yu, Muhua Yi, Xuefeng Wang
Journal: Asian Journal of Pharmaceutical Sciences (2023)

Ovarian cancer (OC) is one of the most common and recurring malignancies in gynecology. Patients with relapsed OC always develop "cascade drug resistance" (CDR) under repeated chemotherapy, leading to subsequent failure of chemotherapy. To overcome this challenge, amphiphiles (P1) carrying a nitric oxide (NO) donor (Isosorbide 5-mononitrate, ISMN) and high-density disulfide are synthesized for encapsulating mitochondria-targeted tetravalent platinum prodrug (TPt) to construct a nanocomposite (INP@TPt). Mechanism studies indicated that INP@TPt significantly inhibited drug-resistant cells by increasing cellular uptake and mitochondrial accumulation of platinum, depleting glutathione, and preventing apoptosis escape through generating highly toxic peroxynitrite anion (ONOO−). To better replicate the microenvironmental and histological characteristics of the drug resistant primary tumor, an OC patient-derived tumor xenograft (PDXOC) model in BALB/c nude mice was established. INP@TPt showed the best therapeutic effects in the PDXOC model. The corresponding tumor tissues contained high ONOO− levels, which were attributed to the simultaneous release of O2•− and NO in tumor tissues. Taken together, INP@TPt-based systematic strategy showed considerable potential and satisfactory biocompatibility in overcoming platinum CDR, providing practical applications for ovarian therapy.
2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation: A Report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines
Authors: José A. Joglar, Mina K. Chung, Anastasia L. Armbruster, Emelia J. Benjamin, Janice Y. Chyou, Edmond M. Cronin, Anita Deswal, Lee L. Eckhardt, Zachary D. Goldberger, Rakesh Gopinathannair, Bulent Gorenek, Paul L. Hess, Mark Hlatky, Gail Hogan, Chinwe Ibeh, Julia H. Indik, Kazuhiko Kido, Fred Kusumoto, Mark S. Link, Kathleen T. Linta, Gregory M. Marcus, Patrick M. McCarthy, Nimesh Patel, Kristen K. Patton, Marco V. Perez, Jonathan P. Piccini, Andrea M. Russo, Prashanthan Sanders, Megan M. Streur, Kevin L. Thomas, Sabrina Times, James E. Tisdale, Anne Marie Valente, David R. Van Wagoner
Journal: Circulation (2023)

The "2023 ACC/AHA/ACCP/HRS Guideline for the Diagnosis and Management of Atrial Fibrillation" provides recommendations to guide clinicians in the treatment of patients with atrial fibrillation.
The gift of preexisting immunity for developing an alternative vaccine strategy
Authors: Kim A Tran, Maziar Divangahi
Journal: Journal of Clinical Investigation (2023)

Despite the worldwide application of vaccination and other antiviral interventions, pulmonary viral infections remain a persistent threat to human health. The 1918 influenza pandemic killed more than 40 million people in just one year, and the SARS-CoV-2 pandemic has killed more than 6.9 million people since 2019. While the current approved COVID-19 vaccines are administered parenterally and induce systemic immunity, they only prevent the progression to severe disease. Thus, other vaccine platforms are still needed for completely preventing the disease and subsequent transmission. In this issue of the JCI, Kawai et al. present an adjuvant-free subunit (RBD-HA) fusion vaccine, which produces robust IgG and IgA antibody responses against SARS-CoV-2, enriched within the nasal cavity, by using the host's preexisting immunity to influenza infection. This preclinical study has tremendous implications for future mucosal vaccine design and provides a roadmap for generating a safer and effective intranasal vaccine against pulmonary infections.